Journal of the American College of Surgeons
Journal of the American College of Surgeons
5 years ago

A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss of Function Polymorphisms and Indoleamine-2,3-Dioxygenase-2

Variation in an individual’s genetic status can impact the development of pancreatic ductal adenocarcinoma (PDA), however the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss of function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. Methods Germline DNA from patients who underwent resection for PDA (n=79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, while the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg (HW) deviation. A genotype frequency set from the 1000 Genomes Project (n=99) was used as a genetic control for genotype distribution comparisons. Results A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared to the expected HW equilibrium was noted (P<0.05). FPC was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (P=0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (Odds Ratio 5.4, 95% CI 1.6-17.6, P<0.01). Gender, age at diagnosis and history of tobacco use were not found to be significantly associated with FPC. Conclusions Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared to the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for PDA and a predictive marker for novel immune checkpoint therapies.

Teaser

Most causes of familial pancreatic cancers (FPC) remain unknown. In our pilot study, we present a strong association between the indoleamine-2,3-dioxygenase-2 loss of function single nucleotide polymorphism genotypes and an increased risk of FPC when compared to a control group. This biomarker may have predictive value and implications for screening high risk individuals.

Publisher URL: www.sciencedirect.com/science

DOI: S1072751518300620

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